Traumatic brain injury (TBI), often referred to as the ?silent epidemic,? is widely discussed in the news today. Among surviving soldiers wounded in Iraq and Afghanistan, TBI accounts for a larger proportion of casualties (> 22%) than in other recent US wars, such as Vietnam (12-14% of all combat casualties), due to improved body armor and field medicine. TBI accounts for a large proportion of the acute and long-term combat casualty care burden. The military loses thousands of man-years in experience, and hundreds of millions of training and education dollars each year due to the effects of TBI in soldiers, including those prematurely returned to active duty as well as soldiers who cannot return to service and add to the already heavy burden on the VA healthcare system. Many young adults never regain premorbid skills or responsibilities after TBI despite intensive and comprehensive rehabilitation efforts on their behalf. The sequelae of TBI are a mixture of cognitive psychomotor and emotional (psychiatric) signs and symptoms, and the emotional and psychological burden on patients and caregivers can be enormous. Repetitive mild TBI (r-mTBI) is one of the most devastating outcomes of the current conflicts, with the consequences to later life health only now beginning to emerge. The diversity of etiology of human TBI poses problems for development and testing of new therapeutics, as does the fact that typically patients will not have sought treatment at the time of injury. Thus the negative sequelae of TBI pathogenesis will often already be well underway by the time interventions are sought. There is a clear need for improved and increased modeling of mTBI in the laboratory, to enable the dissection and evaluation of TBI-dependent molecular responses and identification of better approaches to mitigate the negative outcomes. We have developed several different mouse models of repetitive mild TBI, with different neurobehavioral, neuropathological and biochemical outcomes. They recapitulate features of human TBI and are thus of relevance to a translational platform. Our hypothesis is that treatments showing efficacy with late treatment initiation in multiple different r-mTBI models will have greatest likelihood of success in human trials. We will focus on two potential therapeutics with which we have a lot of experienc; they show efficacy against elements of TBI pathogenesis such as neuroinflammation and tau pathology, and are also potent in mouse models of Alzheimer?s Disease, for which individuals suffering from r-mTBI are at increased risk. We will administer these compounds beginning 3 months after the final injury or sham procedure has been received, and continuing for 3 months with neurological testing of cognition, behavior and motor function prior to euthanasia at the end of the treatment phase. The effects of each treatment will further be assessed with neuropathological and biochemical outcomes and we will rank the ability of each treatment to recover the normal (sham) phenotype for each outcome. We also propose state of the art proteomic and lipidomic profiling of dissected brain regions, to fully characterize the response to injury and to treatment. We will be able to reveal particular molecular pathways as therapeutic targets for TBI drug discovery, based on the unique and overlapping profiles from the different treatments, and the correlation with outcome measures. We have experience in all aspects of targeted drug discovery, and this work will identify new therapeutic avenues and move the r-mTBI research field towards clinical trials of rationalized, preclinically validated treatments. This will be of key importance particularly for long term care, as the treatments should block the secondary TBI sequelae, which lead to many of the devastating clinical presentations that emerge over time.